Synthetic method for preparing penicillins



United States Patent 3,538,083 SYNTHETIC METHOD FOR PREPARINGPENICILLINS Norman H. Grant, Wynnewood, Donald E. Clark, Norristown, andHarvey E. Album, West Chester, Pa., assignors to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledDec. 19, 1967, Ser. No. 691,694 Int. Cl. C07d 99/16 U.S. Cl. 260-239.1 6Claims ABSTRACT OF THE DISCLOSURE Process for preparing a-aminoacylaminopenicillanic acids having antibiotic activity, by reacting6-aminopenicillanic acid or a salt thereof with certain non-labile N-carboxy anhydrides in an organic solvent medium under reflux conditionsand in the presence of an organic amine.

BACKGROUND OF THE INVENTION The invention relates generally to the artof preparing organic chemicals, and more particularly, to the synthesisof a-aminoacylamino penicillanic acids having antibiotic activity.

In U.S. Pat. 2,985,648 there is disclosed a method for producinga-phenyl-a'-aminoacylamino penicillanic acids, including aminobenzylpenicillin (ampicillin) by reacting 6-arninopenicillanic acid With anrat-aminobenzyl acid halide or anhydride, in which the amino group haspreviously been provided with a protecting acyl'group, such as PhCH CO-,or some other functionally equivalent protecting group. To recover thedesired u-aminobenzyl penicillanic acid derivative, it is necessary,subsequently to the acylation of the fi-aminopenicillanic acid by anacylating agent as described, to remove the protecting group from theamino group by catalytic hydrogenation under sufiiciently mildconditions to avoid destruction of the penicillin nucleus. Thus, inaccordance with this known method, it is necessary to proceed throughfour separate operational steps as follows: (1) the amino group of theacylating agent to be used has to be blocked with a protecting acylgroup, (2) the anhydride has to be formed from the protected amino acid,(3) the protected anhydride has to be reacted with 6-aminopenicillanicacid, and finally, (4) the protecting group has to be removed bycatalytic hydrogenation to obtain the desired penicillanic acidderivative.

In U.S. Pat. 3,080,356, there is disclosed a method of producinga-aminobenzyl penicillins by reacting N-carboxy anhydrides with6-aminopenici1lanic acids in an anhydrous organic solvent. However, ascautioned in the patent, the reaction must be carried out at atemperature below about --30 C. owing to the acknowledge extremelyunstable character of the N-carboxy anhydrides (Leuchs anhydrides)therein described.

British patent specification No. 958,824 and Portuguese Pat. No. 40,063similarly disclose processes for preparing a-amino penicillins byreacting N-carboxyanhydrides with 6-amino-penicillanic acid, but in boththe methods described in said patents, a mixture of Water-miscibleorganic solvents and Water is required. Moreover, the Portuguese patentis limited to rat-aminobenzyl penicillins and requires the reactiontemperature to be below 20.

In U.S. Pat. 3,206,455 and U.S. Pat. 3,494,802, methods are shown forpreparing compounds of the type to which the present invention pertains.However, both patents describe the reaction in a totally aqueousenvironment under restrictive conditions of pH.

Patented Nov. 3, 1970 SUMMARY OF THE INVENTION The present invention, inits broadest aspect, comprises the synthesis of penicillins by reactionof certain N-carboxy amino acid anhydrides (NCAs) with6-aminopenicillanic acid (6-APA). More specifically, the presentinvention involves a synthesis of 6-(l-aminocycloalky1-carboxamido)penicillanic acids by reaction of the corresponding NCA with6-APA in an organic solvent in which the 6APA has been dissolved ordispersed with the aid of an organic base. The method may be carried outadvantageously under conditions of temperature easily achieved andmaintained in a production plant.

DESCRIPTION OF THE INVENTION The present invention comprises a processfor producing 6-(1-aminocycloalkylcarboxamido)penicillanic acids of thefollowing formula:

wherein n is an integer from 0 to 4, and R and R are each selected fromthe group consisting of hydrogen,

lower alkyl, lower alkoxy, halogen and nitro; which method comprises;preparing a mixture of an N-car-boxyanhydride of the following formula:

CH2CH2 O GJ (CH2) w-Cg O NHO H 3 wherein each of n, R and R have thesame meaning as in Formula I above, and 6-aminopenicillanic acid, in ananhydrous organic solvent of the group consisting of chlorinatedhydrocarbons, esters, ketones and ethers, having dissolved therein anamine of the group consisting of di(lower)alkyl and tri(lower)alkylamines; and thereafter refluxing said mixture to obtain a compound ofFormula I above.

The N-carboxyanhydrides suitable for use in the process of the presentinvention may be prepared by any of the methods referred to in U.S. Pat.3,206,455, and preferably by the phosgenation procedure specificallydescribed therein. The 6-aminopenicillanic acid may be prepared by themethod also referred to in said patent or by any of the many othermethods now known in the art. The anhydrous organic solvents useful asthe reaction media for the method of invention, while not limitedthereto, may be, for example, methylene chloride, chloroform, ethylacetate, dioxane, acetone, and the like. The amine may be anydi(lower)alkyl or tri(lower)alkyl amine, such as the commerciallyavailable diethylamine, dimethylamine, triethylamine, trimethylamine,dioctylamine and trioctylamine.

The following examples are illustrative of various modes of exercisingthe method of invention, but are not to be considered necessarilylimitative thereof.

EXAMPLE 1 A mixture of 10 g. of 6APA, ml. of methylene chloride, and 6.4ml. of triethylamine was refluxed for 15 minutes. A solution of 5.6 g.of the NCA of l-aminocyclohexane carboxylic acid in 30 ml. of methylenechloride was then added and refluxing allowed to continue for two hours.After standing overnight at 1 the system was filtered, and the filtratewas added to 200 ml. of ethyl room temperature for 13 hours, the systemwas filtered. acetate. After concentration to about 20 ml., 2.7 ml. ofThere was then added to the filtrate 150 ml. of isoproglacial aceticacid in 50 ml. of ethyl acetate was added. panel, the system wasconcentrated to 60 ml., and an The suspension was chilled and filtered.The product, 6- additional 40 ml. of isopropanol was added. After addi-(1-aminocyclohexanecarboxamido)penicillanic acid, was Washed with ethylacetate and dried, giving a weight of tion of 30 ml. of ethyl ether and2.8 ml. of glacial acetic acid, the product precipitated. After washingwith ether 8.25 g. and drying, it weighed 14.8 g. and was 64% pure 6-(1-EXAMPLE 2 aminocyclopentanecarboxamido)penicillanic acid by hy- Amixture of g. of 6-APA, 70 ml. of methylene chlodfOXamate yride, and 6.4ml. of triethylamine was stirred at room 10 temperature for 2 hours andthen filtered. The filtrate was EXAMPLE 6 brought to 100 ml. withmethylene chloride, and 5.3 g. of the NCA of l-aminocyclohexanecarboxylic acid was A ,mlxture of 10 Of 100 P methylene added After 21hours of stirring, assay Showed that 60% chlonde, and 6.4 ml. oftriethylamine was stirred at room of the NCA was still unreacted. Aftera total of 45 hours temperature for 2 hours- There was then added 531 ofthis amount of NCA still remained, showing the need for l'amin,ocyclobutane carboxylic acid and the reac reaction at highertemperatures. After a total of 5 days tion mixture was refluxed for 2hours. It was then cooled however, the reaction was essentiallycomplete, as deterto room temperature and filtered- There was addfidmined by hydroxamic acid assay The mixture was to the filtrate 300 ml.of ethyl acetate, and the entire IIllX- tered, 270 m. of ethyl acetatewas added, and the solution ture, w Concentrated to 9 T w followed, bywas concentrated to a volume of 200 ml. Precipitation of addltlon of ofe acenc acld l chllhng' the product followed addition of 2.8 ml. ofglacial acetic The Productlon Whlch Preclpltated as acid and chillingbelow room temperature. The product, talhecarbmiamido)ReniciuaniF acidweighed 9 and was 6 aminocyclohexane carboxamido) Peniciuanic acid,active against Baczllus subtzlzs 6633, Staphylococcus auwas effectiveagainst Staphylococcus aureous strains reus 6538f) and Esherwhm coll11370- 65 38F and CHP and against Escherichia coli strains 6880 and11370. EXAMPLE 7 EXAMPLE 3 A mixture of 10 g. of 6APA, 100 ml. ofmethylene A fnlxture of 103 70 P methylene chloride, 6.4 ml. oftriethylamine, and 6.5 g. of the NCA chloride, and 14 ml. oftriethylamine was stirred at room f paminocycloheptane carboxylic acidwas refluxed for temperature for 2 hours- There was then added 10 hoursand then allowed to sit at room temperature for of the NCA Ofl-amillocycloheXane carboxylic acid and 8 hours. The system was thenfiltered and 300 ml. of ethyl 3 ml. of gla l acetic acid, and thereaction mixture was acetate was added to the filtrate. The resultingsuspension refluxed for 3 hours The Solutlon was cooled added to wasconcentrated to 125 ml. An additional 75 ml. of ethyl 200 ml. ofdioxane, concentrated to 84 ml., and then acidified with 3 ml. ofglacial acetic acid. The system was then mixed with 300 ml. of ethylether and the resulting acetate was added, followed by 2.7 ml. ofglacial acetic acid; the system was stored in the cold for 5 hours. The

precipitate was removed and dried. This weighed 16.8 g. precipitatingProduct comprising Y 1 pt e and assayed as pure6-(1-aminocyclohexanecarboxcarboxamido)peflicinflnic acid Weighed 8 andWas amido)penicillanic acid by hydroxamate assays. 40 active againstStaphylococcus aureus strains 6538P, 63-

EXAMPLE 4 180 and CHP.

A mixture of 10 g. of 6APA,, 100 ml. of methylene chloride and 6.4 ml.of triethylamine was stirred at room temperature for 1 hour. There wasthen added 5.3 g. of the NCA of l-aminocyclohexane carboxylic acid andthe system was refluxed for 2 hours. The mixture was stored overnight inthe refrigerator, and a precipiate was re- EXAMPLE 8 4,5 The procedureof Example 7 is followed, but the substitution for the NCA ofl-aminocycloheptane carboxylic acid, the respective NCAs listed in TableA below, to obmoved and discarded. An additional 0.7 g. of NCA was tainthe corresponding Penicillins Which are active antiadded to thefiltrate, and the solution was refluxed for anlotlcallyzN-carboxyanhydride Corresponding penicillin l-amino-2-ethyl-cycloheptanecarboxylic acid 6-(l-amin0-2-ethyl-cycloheptanecarboxamido)penicilla iacid 6-(Lamin0-3-methyl-4-ethoxycyclohexanecarboxamido) penieillanicacid. 6 (l-amin0-2-propyl-3-chloro-cyclopentanecarboxamido) penicillanieacid.

6-(l-amino-3-nitro-cyolohexanecarboxanecarboxamido) penicillanic acid.

l-amino-3-methyl-tethoxycyelohexane carboxylic acidl-amin0-2-propyl-3-ehlorocyelopentane carboxyhc acidl-amino-E-nitro-cyclohexane carboxylic acid....

1-amino-3-bromo-eyelohexane carboxylic acid"6-(1-amino-3-br0m0-eyclohexanecarboxamido) penlcillanic a id,l-amino-3-fiu0ro-cyc1ohexane carboxylic acidfi-(l-amino-S-fluoro-cyclohexane carboxamidwpeniclllanic acid.1-amin0-2-n1ethyl-cyclobutane carboxylic acid 6-(1-amm0-2-methyl-cyclbutanecarboxamido) pemcillam'c acid, 1-arnino2-propoxy-cyclohexanecarboxylic acid fr(l-amino-2-pr0p0Xyyc10hexanecarboxamido)pemclllanicacid.

other hour. It was then mixed with 200 ml. of ethyl ace- [Example 9tate, concentrated to 75 ml., and finally acidified with 3 ml. ofglacial acetic acid in ethylacetate. After chilling, a precipitateweighting 8.6 g. was collected. Addition of 65 ether to the filtrategave an additional 3.0 g. The combined produce at this stage was 65%pure 6-(-aminocyclohexanecarboxamido)penicillanic acid by hydroxamateThe procedure of Example 1 is again followed in a series of fourseparate runs, but with the substitution for the methylene chloridesolvent in each run, of the same volume, respectively, of chloroform,ethyl acetate, acetone and dioxane as solvents; in each instance toobtain 6-(1-aminocyclohexane canboxamido)penicillanic acid.

assays.

EXAMPLE 5 Example 10 A mixture of 10 g. of 6APA, 100 ml. of methyleneThe procedure of Example 1 is again followed in a chloride, and 6.4 ml.of triethylamine was stirred at room series of five separate runs, butwith the substitution for temperature for 2 hours. Then 5.52 g. of theNCA of 1- the amine in each run, of the same volume, respectively, ofaminocyclopentane carboxylic acid was added, and the dimethylamine,diethylamine, trirnethylamine, dioctylreaction mixture was refluxed for4 hours. After sitting at amine and trioctylamine.

5 We claim: 1. A process for producing a6-(l-aminocycloalkylcarboxamido)-penicillanic acid of the followingformula:

mula:

OHz-C 2 (H) l (CH2) r-C 2 /O NH(H) 0 II wherein each of n, R and R havethe same meaning as in Formula I above; and

(2) 6-aminopenicillanic acid, in an anhydrous organic solvent of thegroup consisting of chlorinated hydrocarbons, ketones, esters, ethershaving dissolved therein a soluble amine of the group consisting ofdi(lower)alkyl and tri(lower) alkyl amines; and

(B) refluxing said mixture to obtain a compound of Formula I above.

2. A process for producing a6-(1-aminocycloalkylcarboxamido)-penicillanic acid as defined in claim1, wherein the N-carboxyanhydride is that of l-amino-cyclohexanecarboxylic acid.

3. A process for producing a6-(l-aminocycloalkylcarboxamido)-penicillanic acid as defined in claim1, wherein the N-carboxyanhydride is that of l-aminocyclopentanecarboxylic acid.

4. A process for producing a6-(l-aminocycloalkylcarboxamido)-penicillanic acid as defined in claim1, wherein the N-carboxyanhydride is that of l-amino-cyclohcxanecarboxylic acid.

5. A process for producing a6-(l-aminocycloalkylcarboxamido)-penicillanic acid, as defined in claim1, wherein the N-carboxyanhydride is that of l-arninocycloheptanecarboxylic acid.

6. A process for producing a6-(1-aminocycloalkylcarboxamido)-penicillanic acid as defined in claim1, wherein the solvent is methylene chloride and the amine istriethylamine.

References Cited UNITED STATES PATENTS 3,329,675 7/1967 Albuon et a1260239.1

NICHOLAS S. RIZZO, Primary Examiner mg UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 3, 5381083 Dated 3, 97

Inventor) Norman H. Grant, Donald E. Clark. Harvev E. Alburn It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In column 1, line 55, "acknowledge" should read --acknowledged-- Incolumn 3, line 20, "m" should read --ml--;

line 48, "precipiate" should read --precipitate--; line 67, "produce"should read --product-. In column 6, line 15, "l-amino-cyclohexane"should read -l amino-cyclobutane--; line 27, "Alboun et al. should read--Alburn et al.-.

8161MB MD SEALED am) Anon:

Edward M. F100 a l- I .l

